title: High levels of protein C are determined by PROCR haplotype 3.
abstract: BACKGROUND
  Genetic determinants of plasma levels of protein C (PC) are poorly understood. Recently, we identified a locus on chromosome 20 determining high PC levels in a large Dutch pedigree with unexplained thrombophilia. Candidate genes in the LOD-1 support interval included FOXA2, THBD and PROCR.
  
  
  OBJECTIVE
  To examine these candidate genes and their influence on plasma levels of PC.
  
  
  METHODS
  Exons, promoter and 3'UTR of the candidate genes were sequenced in 12 family members with normal to high PC levels. Four haplotypes of PROCR, two SNPs in the neighboring gene EDEM2 and critical SNPs encountered during resequencing were genotyped in the family and in a large group of healthy individuals (the Leiden Thrombophilia Study (LETS) controls). Soluble endothelial protein C receptor (sEPCR) and soluble thrombomodulin (sTM) plasma levels were measured in the family.
  
  
  RESULTS
  PROCR haplotype 3 (H3) and FOXA2 rs1055080 were associated with PC levels in the family but only PROCR H3 was also associated with plasma levels in the healthy individuals. Carriers of both variants had higher PC levels than carriers of only PROCR H3 in the family but not in healthy individuals, suggesting that a second determinant is present. EDEM2 SNPs were associated with PC levels, but their effect was small. PC and sEPCR levels were associated in both studies. sTM was not associated with variations of THBD or PC levels.
  
  
  CONCLUSIONS
  Chromosome 20 harbors genetic determinants of PC and sEPCR levels and the analysis of candidate genes suggests that the PROCR locus is responsible.
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Pintao
authors.forename: S
authors.initials: S
authors.lastname: Roshani
authors.forename: M C H
authors.initials: MC
authors.lastname: de Visser
authors.forename: C
authors.initials: C
authors.lastname: Tieken
authors.forename: M W T
authors.initials: MW
authors.lastname: Tanck
authors.forename: I M
authors.initials: IM
authors.lastname: Wichers
authors.forename: J C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: F R
authors.initials: FR
authors.lastname: Rosendaal
authors.forename: S
authors.initials: S
authors.lastname: Middeldorp
authors.forename: P H
authors.initials: PH
authors.lastname: Reitsma
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D002675:Child, Preschool; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D000074283:Endothelial Protein C Receptor; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D010375:Pedigree; D011401:Promoter Regions, Genetic; D011486:Protein C / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics*; D018180:Thrombomodulin / Q000097:blood
chemical_list: D020413:3' Untranslated Regions; D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011486:Protein C; D011956:Receptors, Cell Surface; D018180:Thrombomodulin